Glycolysis is the metabolic pathway that converts glucose into pyruvate. The free energy released in this process is used to form the high-energy compounds ATP and NADH. Increased aerobic glycolysis is seen in a variety of cancer cells, a phenomenon known as the Warburg theory. Under aerobic conditions, some tumor cells produce as much as 60% of their ATP through glycolysis (Nakashima et al., Cancer Res. (1984) 44:5702-5706) as opposed to normal cells which normally generate ATP through mitochondrial oxidative phosphorylation. In addition to increased aerobic glycolysis, increased glycolysis is also seen in tumors that reach a size that exceeds the capacity of blood supply due to hypoxia. For a review of the Warburg theory and implications thereof, see, e.g., Chen et al., J. Bioenerg. Biomenzbr. (2007) 39:267-274.
Glucagon-like peptide-1 (GLP-1) is an important hormone and a fragment of the human proglucagon molecule. GLP-1 is rapidly metabolized by a peptidase (dipeptidylpeptidase IV or DPP-IV). A fragment of GLP-1, glucagon-like peptide-1 (7-36) amide (also known as GLP-1 (7-36) amide, glucagon-like insulinotropic peptide, or GLIP) is a gastrointestinal peptide that potentiates the release of insulin in physiologic concentrations (Gutniak et al., N Engl J Med (1992) 14:326(20):1316-22). Food intake, as well as stimulation of the sympathetic nervous system, stimulates secretion of GLP-1 in the small intestine of mammals. Further, GLP-1 stimulates the production and secretion of insulin, the release of somatostatin, glucose utilization by increasing insulin sensitivity, and, in animal studies, also stimulates beta-cell function and proliferation. GLP-1(7-36)amide and GLP-1(7-37) normalize fasting hyperglycemia in type 2 diabetic patients (Nauck, M. A., et al., Diabet. Med. 15(11):937-45 (1998)).
Exendin-4, a GLP-1 receptor agonist, is a molecule purified from Heloderma suspectuni venom (Eng, et al., Biol. Chem. (1992) 267:7402-7405) and shows structural relationship to the hormone GLP-1(7-36)amide. Exendin-4 and truncated exendin-(9-39)amide specifically interact with the GLP-1 receptor on insulinoma-derived cells and on lung membranes (Goke et al., J Biol. Chem. (1993) 268:19650-19655). Exendin-4 has approximately 53% identity to human GLP-1 (Pohl, et al., J. Biol. Chem. (1998) 273:9778-9784). Unlike GLP-1, however, exendin-4 is resistant to degradation by DPP-IV. A glycine substitution confers resistance to degradation by DPP-1V (Young, et al., Diabetes (1999) 48(5):1026-1034).
The increased dependency of cancer cells on the glycolytic pathway is an important metabolic difference between normal and malignant cells. The present invention provides a unique solution to disrupting cancer cell energy reliance on the glycolytic pathway.